The main hypothesis of this proposal is that the severe inflammation and tissue damage seen in mucosal leishmaniasis (ML) is associated with a "biased" immune response and influenced by the parasite and host genetic background. ML is characterized by involvement of the nasal mucosa either concomitantly with cutaneous leishmaniasis (CL) or months or years after resolution of the primary lesion. The disease is caused by L. braziliensis and occurs in 3-4% of CL patients. The major aims are: 1} to characterize systemic and "in situ" immunopathological response in ML and CL patients. The synthesis and expression of cytokines will be detected in peripheral blood mononuclear cells and in the lesions. The cell source of cytokine and regulation of immune response by modulatory cytokines, neutralizing antibodies and leishmania antigen will also be analyzed. 2) to evaluate if parasite factors are influencing the disease outcome by subtyping L. braziliensis isolates from CL and ML using molecular biology tools. Once different strains are identified, we propose to test those isolates for virulence using "in vitro" assays of infectivity and survival to oxidants. The immune response induced by different L. braziliensis isolates will be also analyzed. 3) to conduct a family study to determine host genetic contributions to disease outcome. A family cohort will be established for statistical analysis of genetic or environmental contribution to disease outcome and a DNA bank of all family members will be stored anticipating the need of a future genome wide scan. The unique aspects of our project are: 1) the interaction of a selected group of investigators with large experience in field and laboratory work in leishmaniasis; 2) the comparison between peripheral and tissue responses in the same patients; 3) the access to a large group of patients; 4) the proposed studies addressing cell phenotype and function, and 5} the study of parasite isolates from distinct clinical forms of disease. Studies proposed will clarify host immune response in ML and shed light on the potential host and parasite factors influencing disease outcome in L. braziliensis infection.